BioModels Database

August 2011, model of the month by Ishan Ajmera
Original model: BIOMD0000000239

Increasing incidence of T2DM and its related complication has driven the attention of many research groups worldwide. Certainly, many studies and approaches have been undertaken towards understanding the role of insulin and glucagon in maintaining the blood glucose level within an optimal range [1]. But, the complex nature and multiple aetiology of this systemic disease, has proved to be a major barrier in development of a standard therapeutic measures leading to its control. Thus, there exists a wide arena for research towards addressing this spreading epidemic.

A fundamental property of pancreatic islet β-cells is to secrete insulin in response to changes in blood glucose concentrations. A complete understanding of the biochemical mechanism of glucose-stimulated insulin secretion (GSIS) is extremely valuable for the development of new therapies for both major forms of diabetes. Notably, this critical homeostatic process involves number of biochemical pathways such as glycolysis, the TCA cycle, the respiratory chain, NADH shuttles and pyruvate cycle, leading towards regulating blood glucose levels (Figure 1).

Figure 2: Wire diagram of the kinetic network involved in GSIS. Figure taken from [2].

Given the advantages of developing a mathematical model for a biological system, numbers of models related to GSIS system have been developed. However, these models are limited in the pathways that are considered, so that a more comprehensive approach is now necessary.

Jiang et al [2,BIOMD0000000239] has developed a quantitative, detailed kinetic model of the core processes responsible for GSIS by considering complete insulin secretion pathway starting from glycolysis to ATP production as seen in Figure 2. Significantly, the model developed elucidates the relationship between ATP output and glucose input concentrations and the oscillations of metabolite concentration in the glycolysis pathway. As the model represents the situation in mouse pancreatic beta cells, the species specific parameters applied to the model aid our understanding towards the mouse model of diabetes and the relationship of this mouse models to human disease state. It can also serve as a tool towards understanding genetic and biochemical data in mouse models of T2DM and can be used for studying insulin secretion dynamics in humans.

Consistent with previous experimental and modeling studies, current model shows expected behaviour in its outputs, including the response of ATP production to starting glucose concentration and the induction of oscillations of metabolite concentrations in the glycolysis pathway and in ATP and ADP concentrations as required for stimulation of Ca2+ transport in beta cells (Figure 3). In addition, identification of choke points and parameter sensitivity analysis concluded the significance of glycolysis pathways in proper functioning of GSIS system. Interestingly, this model was also found to be robust to deletion of malic enzyme activity , which is absent in mouse beta cells and can serve as the basis for interspecies difference analysis.

To further understand the processes leading to T2DM, authors also have identified the scope for extending this model by including additional processes such as generation and detoxification of reactive oxygen species and downstream process leading to transport of calcium in response to fluctuations in ATP concentration and eventual export of insulin. On this note, more recently, Fridlyand and Philipson [3] have developed more comprehensive model of the core processes of β-cell cytoplasmic and mitochondrial energetic with most recent experimental characterizations of the majority of processes in the model to insure accuracy. The model developed predicts the role of mitochondrial control mechanisms in insulin secretion and ROS generation in the beta cell and can provide a more complete understanding of beta-cell glucose-sensing central to the physiology and pathology of pancreatic β-cells.

Although, last decade marked significant development of diverse range of mathematical models explaining various aspects of diabetes, the need for more comprehensive mechanistic models for diabetes and its complications has been recognized. Thus, motivating systems biology research community to develop more integrative modeling approaches meant to tackle with the biological problems like diabetes.

Figure 2: BIOMD0000000239. Dynamic simulation results of some metabolites in the GSIS network.

Bibliographic References

Boutayeb A and Chetouani A. A critical review of mathematical models and data used in diabetology. BioMedical Engineering Online 5(43), 2006. [CiteXplore]